The present study provides further evidence for an epidemiological association between IBD and a subsequent diagnosis of MS in a cohort of primary care patients in Germany. In addition, this association was stronger in men than in women. Our data are in line with previous reports, showing an increased incidence of MS among IBD patients [16, 17]. Among these, a recently meta-analysis revealed a risk ratio of 1.91, which is comparable with our findings. Interestingly, the authors also observed an increased incidence of IBD among patients with MS, underlining the close pathophysiological link between the two conditions [16].

Reports exploring a possible relationship between MS and IBD date back to the early 1980s, whenan increased prevalence of MS was described for women who underwent total colectomy for UC or CD in the United Kingdom [18]. Subsequent studies where able to corroborate this association. A recent systematic review and meta-analysis highlighted not only an increased prevalence of MS in patients with IBD, but also a heightened prevalence of IBD in patients with MS [4]. Despite longstanding evidence for an epidemiological association between MS and IBD, the mechanisms behind this association are far from understood. This poses a significant challenge in disease management of patients with comorbid MS and IBD, as treatment options for one condition may adversely affect the other. Specifically, the use of interferon-β, a cytokine commonly used to treat MS, has been associated with increased severity of IBD [19]. Of note, the evidence regarding the effect of interferon treatment on symptoms in certain patients with IBD is equivocal, with some studies suggesting a potential benefit [19, 20]. In contrast, TNF-α antagonists, which are effective for treating IBD, have been shown to worsen the severity of MS [9, 21]. While treatments with TNF-α antagonists were debated as one possible explanation for the observed epidemiological association between IBD and MS, prior studies reported an increased risk for subsequent MS diagnosis even in the absence of anti-TNF-α therapy. For instance, one study analyzing white matter hyperintensities was able to demonstrate a significantly higher incidence of white matter T2-hyperintensities in patients with CD compared to controls, despite displaying no correlation to anti-TNF therapy [22]. Furthermore, in a retrospective analysis examining a total of 9095 IBD patients, anti-TNF-α therapy did not increase the risk of subsequent diagnosis of clinical idiopathic inflammatory demyelinating disease [23]. Finally, it is noteworthy that natalizumab, a highly specific alpha4-integrin antagonist approved for the treatment of MS [24], has also been shown to induce clinical remission in patients with moderately to severely active CD [25, 26], suggesting that synergistic effects may be useful in patients with CD and MS. However, natalizumab is not approved for the treatment of CD in Europe [27].

In recent years, shared genetic patterns in autoimmune diseases—and in particular between MS and IBD—have gained rising attention as a possible contributor to the observed association between these two conditions. Besides an increased familial occurrence of autoimmune disorders in general and overlapping genetic loci [28], there is also a growing number of identified shared genetic polymorphisms between MS and IBD [6, 29]. For instance, one study was able to identify common genetic polymorphisms in CD4 + T cells and CD8 + cytotoxic T cells that may contribute to the comorbid association between MS and IBD [30]. Specifically, IL23A, a gene involved in CD4 + T cell function, has been implicated in the pathophysiology of both MS and IBD. In addition, PTGER4—encoding the prostaglandin E2 receptor 4—has been found to be involved in susceptibility to both MS and CD and was highly expressed in CD8 + cytotoxic T cells. These findings suggest a possible role for these cell types and genes in shared immune regulation pathways that contribute to the development of MS and IBD.

Besides genetic predisposition, gut microbial dysbiosis and dysfunction of the intestinal barrier have been linked to the onset and progression of MS [31, 32]. Of note, in context of both MS and IBD, a significant association with the prevalence of Epstein-Barr virus (EBV) has been reported. In MS, the risk of disease initiation was significantly increased after infection with EBV, but not other similarly transmitted viruses such as cytomegalovirus [33]. For IBD, we were able to show a similar significant association with infectious mononucleosis and CD in a previous study [34]. Interestingly, this relationship was only observed in female patients. In contrast, the present study demonstrates a significant association between CD and MS only in male patients. While sex-differences in comorbidities of MS have been described before, these studies have established higher prevalence of IBD in female patients with MS, although statistical significance was not reached [8]. In general, the role of sex hormones is of critical importance in autoimmune and inflammatory diseases such as IBD or MS. For instance, testosterone has been shown to exert protective effects and to improve inflammatory markers regarding various autoimmune diseases [35]. In the case of MS, higher serum levels of testosterone may decrease pro-inflammatory cytokines, such as TNF-α and INF-γ, and induce a shift in T helper cell (Th) profile from a Th1-dominant to an Th2-dominant type, while also suppressing lymphocyte proliferation and immunoglobulin production [36].

One other potential commonality between MS and IBD is vitamin D deficiency. Vitamin D which is an essential nutrient regulating the immune system and reducing inflammation has been shown to improve flares in IBD and disease progression in MS [37, 38]. Furthermore, sufficient serum vitamin D levels have been shown to decrease the risk of developing MS or IBD [39, 40]. The connection between Vitamin D and MS and IBD, however, is still not very well understood even though sufficient intake of vitamin D may improve both conditions.

There are several limitations to our study that must be considered. First, in an outpatient treatment setting, we acknowledge that some diagnoses may be subject to incorrect coding or misclassification by the attending physician. Second, the Disease Analyzer database does not provide data on pertinent factors such as the socioeconomic status of patients (e.g., education and income) or lifestyle-related risk factors (e.g., smoking, alcohol consumption and physical activity) which may potentially introduce bias to our analysis. Third, there was no available information regarding the methods of diagnosis of either MS or IBD, and it is possible that diagnoses recorded by the general practitioner in charge may have been previously made by a specialist or in a hospital setting without the GP's involvement in the diagnostic process. Fourth, in GP practices, no information on the individual therapy for IBD such as biological prescription was recorded as this therapy is usually given by gastroenterologists. Therefore, our study cannot answer the important question of whether or not, e.g., anti-TNF treatment might influence the incidence of MS in our cohort of patients. Fifth, the dataset does not contain detailed information on the presence of other extraintestinal disease manifestation of IBD or the particular phenotypes of IBD and MS. Sixth, the matching design used in the study, can cause the so-called overmatching what can lead to an increased similarity between cases and controls in terms of exposure levels, with a consequence what a study population can become not representative of the broader population. Lastly, due to the study design, we can only make assumptions about associations between variables and cannot infer any causal relationships.

In summary, this study provides evidence for a significant association between IBD and subsequent diagnosis of MS in a large outpatient cohort in Germany. These findings may provide important implications for the management and treatment of patients with IBD and MS, although future studies are needed to, e.g., evaluate the specific impact of IBD treatment on this association.